The Relationship between Peripheral Blood MiR-409-3p，MiR-6861-5p and the Prognosis of TACE in Patients with Hepatocellular Carcinoma
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摘要:
目的 探究外周血miR-409-3p、miR-6861-5p与经导管动脉化疗栓塞术（transcatheter arterial chemoembolization，TACE）后肝细胞肝癌（hepatocellular carcinoma，HCC）患者预后的关系。 方法 选取武警四川省总队医院2019年1月—2022年4月收治HCC患者200例作为HCC组，采用TACE治疗，对照组由同期招募的200名健康志愿者组成。比较两组外周血miR-409-3p、miR-6861-5p表达水平及HCC组不同特征患者外周血miR-409-3p、miR-6861-5p表达水平，随访3年，统计HCC患者TACE治疗预后，比较不同预后、疗效患者外周血miR-409-3p、miR-6861-5p表达及变化值，采用COX回归方式，分析其预后影响因素，绘制受试者工作特征（receiver operating characteristic curve，ROC）曲线分析HCC患者miR-409-3p、miR-6861-5p预测TACE治疗预后的效能，Kaplan-Meier生存曲线分析miR-409-3p、miR-6861-5p与HCC患者TACE治疗预后的关系。 结果 HCC组外周血miR-409-3p表达水平低于对照组，miR-6861-5p表达水平高于对照组（P < 0.05）；200例患者随访3年，随访期间，失访9例，其余患者中101例（52.88%）因HCC死亡。多因素COX回归分析结果显示，肿瘤数目、门静脉癌栓、首次TACE疗效、后续接受系统治疗及外周血miR-409-3p、miR-6861-5p表达均为HCC患者预后独立影响因素（P < 0.05），且校正了肿瘤数目、门静脉癌栓、首次TACE疗效、后续接受系统治疗后，ΔmiR-409-3p、ΔmiR-6861-5p表达仍与HCC患者预后独立相关（P < 0.05）；ROC曲线显示，ΔmiR-409-3p、ΔmiR-6861-5p单独预测TACE治疗预后的曲线下面积（area under the curve，AUC）分别为0.766、0.750，二者联合预测HCC患者TACE治疗预后的曲线下面积为0.863，明显大于各指标单独预测（P < 0.05）。 结论 外周血miR-409-3p和miR-6861-5p是HCC重要的潜在调控分子，其治疗前后的动态变化（Δ值）与TACE疗效及患者生存密切相关。联合检测二者Δ值构建的预测模型具有较高的临床转化潜力，有望用于TACE治疗前高危患者的筛选及治疗后疗效的早期评估和动态监测。 -
关键词:
- 肝细胞肝癌 /
- miR-409-3p /
- miR-6861-5p /
- 经导管肝动脉化疗栓塞 /
- 预后
Abstract:Objective To investigate the relationship between peripheral blood miR-409-3p, miR-6861-5p and the prognosis of patients with Hepatocellular carcinoma （HCC） after Transcatheter arterial chemoembolization （TACE）. Methods Two hundred HCC patients admitted to the Sichuan Provincial Armed Police Corps Hospital from January 2019 to April 2022 were selected as the HCC group and treated with TACE. Another 200 healthy subjects were selected in the same period as the control group. The expression levels of miR-409-3p and miR-6861-5p in peripheral blood were compared between the two groups and among HCC patients with different clinical characteristics. The expression levels of peripheral blood miR-409-3p and miR-6861-5p were compared between the two groups and patients were followed for 3 years to assess TACE treatment outcomes. Expression levels and changes of peripheral blood miR-409-3p and miR-6861-5p were compared among patients with different prognoses and treatment responses. COX regression was used to analyze the prognostic factors. Receiver operating characteristic （ROC） curves were plotted to analyze the efficacy of miR-409-3p and miR-6861-5p in predicting the prognosis of TACE treatment in HCC patients. Kaplan-Meier survival curves were used to analyze the relationship between miR-409-3p, miR-6861-5p and the prognosis of TACE in HCC patients. Results Compared with the control group, the expression level of miR-409-3p in peripheral blood in the HCC group was lower, while the expression level of miR-6861-5p was higher （P < 0.05）. Of the 200 patients followed for 3 years, 9 patients were lost to follow-up. Among the remaining patients, 101 （52.88%） died from HCC. The results of multivariate COX regression analysis showed that the number of tumors, portal vein tumor thrombus, initial TACE response, subsequent systemic treatment, and the expression levels of miR-409-3p and miR-6861-5p in peripheral blood were independent prognostic factors for HCC patients （P < 0.05）. After adjusting for the number of tumors, portal vein tumor thrombus, initial TACE response, and subsequent systemic treatment, the expression of ΔmiR-409-3p and ΔmiR-6861-5p was still independently associated with the prognosis of HCC patients （P < 0.05）. ROC curve showed that the Area under the curve （AUC） of ΔmiR-409-3p and ΔmiR-6861-5p alone in predicting the prognosis of TACE was 0.766 and 0.750, respectively. The area under the curve of the combined prediction of the two markers yielded an AUC of 0.863, which was significantly larger than that of either index alone （P < 0.05）. Conclusion Peripheral blood miR-409-3p and miR-6861-5p are important potential regulatory molecules for HCC, and their dynamic changes before and after treatment （Δ value） are closely related to TACE efficacy and patient survival. The predictive model constructed by the combined detection of the two Δ values has a high clinical transformation potential, which is expected to be used for the screening of high-risk patients before TACE treatment and the early evaluation and dynamic monitoring of the efficacy after treatment, so as to provide a new evidence-based basis for the realization of individualized treatment management of HCC. -
图 1 外周血miR-409-3p、miR-6861-5p单独及联合预测HCC患者TACE治疗预后的ROC曲线
Figure 1. ROC Curves for the individual and combined prediction of TACE prognosis in HCC patients using peripheral blood miR-409-3p and miR-6861-5
表 1 引物序列
Table 1. Primer sequences
引物名 正向引物（5'-3'） 反向引物（5'-3'） miR-409-3p CGGAATGTTGCTCGGTGA AGTGCAGGGTCCGAGGTAT miR-6861-5p ACACTCCAGCTGGGACTGGTAGGTGGGC GTGCAGGGTCCGAGGT U6 CTGGCATCCGCTGGAGA TTCGGTTGTCGATATTCGGT 
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表 2 两组基线资料比较[n（%）/（$ \bar x \pm s $）]
Table 2. Comparison of baseline data between the two groups [n（%）/（$ \bar x \pm s $）]
组别 n 性别（n） 年龄（岁） 男 女 HCC组 200 148（74.00） 52（26.00） 60.43 ± 6.24 对照组 200 145（72.50） 55（27.50） 59.41 ± 6.23 t/χ2 0.115 1.636 P 0.735 0.103
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表 3 两组外周血miR-409-3p、miR-6861-5p表达水平比较（$ \bar x \pm s $）
Table 3. Comparison of miR-409-3p and miR-6861-5p expression levels in peripheral blood between the two groups （$ \bar x \pm s $）
组别 n miR-409-3p miR-6861-5p HCC组 200 0.69 ± 0.10 1.92 ± 0.30 对照组 200 1.00 ± 0.06 1.00 ± 0.05 t 37.593 42.779 P <0.001* <0.001* *P < 0.05。
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表 4 不同预后患者临床特征比较[n（%）]
Table 4. Comparison of clinical Characteristics among patients with different prognoses[n（%）]
病理特征 n 死亡（n=101） 存活（n=90） χ2 P 性别 0.522 0.470 男 144 74（73.27） 70（77.78） 女 47 27（26.73） 20（22.22） 年龄（岁） 1.913 0.167 ≤55 75 35（34.65） 40（44.44） >55 116 66（65.35） 50（55.56） 乙肝表面抗原 0.160 0.690 阳性 130 70（69.31） 60（44.44） 阴性 61 31（30.69） 30（55.56） 肝硬化 0.110 0.740 有 88 50（49.50） 38（42.22） 无 103 51（50.50） 52（57.78） 肿瘤数目 13.958 <0.001* 单发 120 51（50.50） 69（76.67） 多发 71 50（49.50） 21（23.33） 肿瘤长径（cm） 8.317 0.004* 3～5 81 33（32.67） 48（53.33） >5 110 68（67.33） 42（46.67） 甲胎蛋白（ng/mL） 8.044 0.005* ≤400 120 54（53.47） 66（73.33） >400 71 47（46.53） 24（26.67） Child-Pugh分级 1.030 0.310 A级 151 77（76.24） 74（82.22） B级 40 24（23.76） 16（26.67） 门静脉癌栓 8.609 0.003* 有 56 40（39.60） 16（82.22） 无 135 61（60.40） 74（17.78） 首次TACE疗效 13.065 <0.001* 疾病稳定/进展 51 38（37.62） 13（14.44） 客观缓解 140 63（62.38） 77（85.56） 后续接受系统治疗 4.229 0.040* 是 160 81（80.20） 89（87.78） 否 31 20（19.80） 11（12.22） *P < 0.05。
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表 5 HCC组不同预后患者外周血miR-409-3p、miR-6861-5p表达水平比较（$ \bar x \pm s $）
Table 5. Comparison of expression levels of miR-409-3p and miR-6861-5p in peripheral blood among HCC patients with different prognoses （$ \bar x \pm s $）
组别 n miR-409-3p miR-6861-5p 治疗前 治疗后 Δ值 治疗前 治疗后 Δ值 死亡 101 0.65 ± 0.07 0.82 ± 0.09 0.17 ± 0.05 2.05 ± 0.30 1.52 ± 0.44 0.53 ± 0.15 生存 90 0.73 ± 0.09 0.97 ± 0.15 0.24 ± 0.07 1.77 ± 0.25 1.12 ± 0.32 0.65 ± 0.20 t 6.895 8.483 8.015 6.462 7.109 5.509 P <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* *P < 0.05。
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表 6 不同首次TACE疗效患者外周血miR-409-3p、miR-6861-5p表达及变化值比较（$ \bar x \pm s $）
Table 6. Comparison of expression levels and change values of miR-409-3p and miR-6861-5p in peripheral blood of among patients with different initial TACE responses （$ \bar x \pm s $）
疗效 n miR-409-3p miR-6861-5p 治疗前 治疗后 Δ值 治疗前 治疗后 Δ值 客观缓解 75 0.75 ± 0.08 0.98 ± 0.10 0.23 ± 0.07 1.78 ± 0.26 1.02 ± 0.30 0.76 ± 0.25 疾病稳定/进展 116 0.66 ± 0.07 0.83 ± 0.08 0.17 ± 0.05 2.02 ± 0.28 1.53 ± 0.32 0.40 ± 0.13 t 7.188 9.929 5.902 5.352 9.905 10764 P <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* *P < 0.05。
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表 7 HCC患者预后影响因素分析
Table 7. Analysis of prognostic factors in HCC patients
变量 单因素 多因素（模型1） 多因素（模型2） HR 95% CI P HR 95% CI P HR 95% CI P 性别（男 vs 女） 1.037 0.948～1.135 0.425 - - - - - - 年龄（>55岁 vs ≤55岁） 1.182 0.891～1.568 0.247 - - - - - - 乙肝表面抗原（阳性 vs 阴性） 1.208 0.973～1.499） 0.087 - - - - - - 肝硬化（有 vs 无） 1.165 0.940～1.444 0.163 - - - - - - 肿瘤数目（多发 vs 单发） 2.350 1.680～3.286 <0.001* 2.012 1.433～2.824 <0.001* - - - 肿瘤长径（>5 cm vs ≤5 cm） 2.024 1.447～2.831 <0.001* 1.332 0.920～1.929 0.127 - - - 甲胎蛋白
（>400 ng/mL vs ≤400 ng/mL）2.276 1.640～3.157 <0.001* 1.315 0.918～1.885 0.137 - - - Child-Pugh分级（B级 vs A级） 1.308 0.941～1.820 0.111 - - - - - - 门静脉癌栓（有 vs 无） 3.150 2.237～4.436 <0.001* 2.545 1.756～3.687 <0.001* - - - 首次TACE疗效
（疾病稳定/进展 vs 客观缓解）2.869 2.017～4.080 <0.001* 2.243 1.543～3.262 <0.001* - - - 后续接受系统治疗 （是 vs 否） 0.518 0.378～0.709 <0.001* 0.607 0.439～0.840 0.003* - - - ΔmiR-409-3p 0.718 0.648～0.796 <0.001* 0.822 0.730～0.925 0.001* 0.850 0.755～0.958 0.008* ΔmiR-6861-5p 1.383 1.269～1.507 <0.001* 1.218 1.107～1.341 <0.001* 1.185 1.075～1.306 <0.001* *P < 0.05；多因素模型2在模型1基础上校正了其他混杂因素。
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表 8 ΔmiR-409-3p、ΔmiR-6861-5p对HCC患者TACE治疗预后的预测价值
Table 8. Predictive value of ΔmiR-409-3p and ΔmiR-6861-5p for the prognosis of HCC patients treated with TACE
指标 AUC 截断值 95%CI 约登指数 敏感度（%） 特异度（%） P ΔmiR-409-3p 0.766 0.20 0.699～0.824 0.403 65.33 75.00 <0.001* ΔmiR-6861-5p 0.750 0.58 0.683～0.810 0.396 70.67 68.97 <0.001* 联合预测 0.863 0.806～0.909 0.595 70.67 88.79 <0.001* *P < 0.05。
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